1. Field of the Invention
This invention relates to direct compression tabletting compositions and the pharmaceutical tablets produced therefrom. More particularly, this invention relates to improved direct compression tabletting compositions prepared from a uniquely agglomerated mixture of a crystalline sugar such as dextrose monohydrate, sucrose, or blends of sucrose and dextrose and a maltodextrin having a measurable dextrose equivalent value not substantially above about 25 and a descriptive ratio of at least about 2. The improved direct compression tabletting compositions are capable of being directly compressed into commercially acceptable and hard tablets. The new direct compression tablets can be used as the sole binder disintegrant without the aid of other adjuvants ordinarily used for this purpose.
2. Description of the Prior Art
The compressed tablet is the most popular unit dosage form for medicinal substances. The tablet as a dosage form can be traced to well over 1,000 years ago when a procedure for molding solid forms containing medicinal ingredients was recorded. As a result of the introduction of new carriers and compression vehicles, tablets are replacing all forms of pills, powders and capsules. Accordingly, tablets presently represent the largest production volume of all pharmaceuticals.
The reason for the widespread use of tablets is apparent, since tablets enable: (1) administration of medication in an accurate dose, (2) fast and accurate dispensing with less chance of error and contamination, (3) ease of administration, (4) administration in a form in which the time and area of contact between the active ingredient and the taste buds is reduced, thus obviating the physiological problems associated with the oral administration of drugs that possess a bitter taste and, in the case of coated tablets, with drugs that possess a disagreeable odor, (5) release of drugs of specific locations in the gastro-intestinal tract to: (a) prevent degradation of drugs sensitive to the low pH environment in the stomach, (b) prevent release of drugs that irritate the gastric mucosa in the stomach, (c) facilitate local action or preferential absorption at specific sites in the tract, (6) enhance stability by effecting a marked reduction in the surface of the drug exposed to the environment, (7) rapid production, and (8) economy and ease in storage, packaging and shipping.
It is well-known that in order to form a tablet of a given material, the material must possess fluidity and compressibility. It is essential that the material must flow uniformly from the hopper to the dies of the tablet press. Any defective flow of the material will affect the weight of the tablets, content uniformity, disintegration time, hardness, friability, and also the bioavailability of the active ingredient.
There are currently three basic methods for tabletting. They are the wet granulation method, the dry granulation method, and the direct compression method. The direct compression method is by far the desired method from the standpoint of processing procedures, equipment and materials. However, only a very limited number of pharmaceutically used substances possess enough cohesive strength and flowability to allow direct compression without previous granulation. Certain crystalline materials, such as potassium bromide and potassium chloride can be compressed without preliminary treatment. Also, aspirin, phenolthaline, and chlorohydrate can be directly compressed.
It has been stated that the ideal material to compress would be composed of crystals which, at the moment of compression, behaved like clay rather than rubber. The crystals should be such that on release of pressure they should not rebound into their original shape. Generally, most materials possess both plastic and elastic deformation properties. Therefore, most materials are not suitable for direct compression without previous granulation.
It has been estimated that about 20% of the materials used for tabletting in the pharmaceutical field may be compressed directly. In order to use this method to a considerable extent, many more materials should be modified by treatment or by use of additives. Modification may be undertaken either by treating the material in some special way during earlier stages of preparation, or by adding a binder or excipient material which will surround the active ingredient and form an easily compressible carrier.
An ideal direct compression vehicle should possess the following properties: (1) low elastic modulus, (2) high dislocation density, (3) inert, non-potent and non-toxic, (4) high degree of plastic deformation, (5) colorless, odorless, tasteless or without disagreeable taste, (6) free-flowing, (7) compatible with active ingredients and common additives like lubricants, colors, etc., (8) fast disintegration properties, or should not delay the bioavailability of the drug, (10) limited range of particle size distribution, (11) stable against effects of aging, and (12) reworkable and should possess high carrying capacity for active medicinal agents.
There are currently several available direct compression vehicles. They include spray-dried lactose; anhydrous lactose; microcrystalline cellulose; dicalcium phosphate dihydrate, unmilled; Cellutab; spray-congealed mannitol; Emcompress; Magnapol; Frodex; and Di Pac.
Microcrystalline cellulose is a natural cellulose in specially processed form which makes it digestible. It normally produced good tablets with fast disintegration and drug release properties. It has been found to give better results if stored in a dry condition before use -- exposure to a slightly humid atmosphere makes it compress less easily. It is quite fluffy by nature.
Spray-dried lactose has a heavy appearance when poured and is spherical in shape. It cannot be reworked, as the spherical shape is lost when ground. It has been disclosed that spray-dried lactose with 5-10% maize starch as a disintegrant and 0.5% magnesium stearate as a lubricant forms a useful direct compression base. However, it has the tendency to get brown in the presence of moisture, amines, phosphates, lactates and acetates. Borates and the stearate lubricants tend to retard the browning.
Dicalcium phosphate dihydrate has good flow and compressibility properties. The tablets from dicalcium phosphate dihydrate are also easily embossed. The increased flow is believed to be due to its high density. It cannot be reworked. Due to its alkaline pH, stability of ingredients like Vitamin C or aspirin may be affected.
The vehicle mannitol, absorbs heat from the surroundings when going into solution, and results in good "mouth feel". Thus, it is commonly used in chewable tablets. It has been reported that a change in the compression characteristics of mannitol occurs when spray-congealing the product.
The vehicle known in the art as Cellutab is a spray-dried dextrose product. It has excellent flow characteristics. It is relatively coarse compared to other vehicles and contains approximately 8% moisture.
The product known in the art as Emcompress is essentially a blend of dicalcium phosphate dehydrate, unmilled; starch; Avacil; and magnesium stearate. It is free-flowing, self-lubricating and possesses good compression characteristics.
The vehicle known in the art as Di Pac is a mixture of a crystalline sugar and a maltodextrin. The preparation of this product is generally described in U.S. Pat. No. 3,642,535, granted Feb. 15, 1972.
Although the direct compression method for preparing tablets is by far the method of choice by virtue of its simplicity, this method has several limitations which have hampered its use in the tabletting industry. These limitations include: (1) differences in the particle size, and bulk density between the diluent and the active ingredient may lead to stratification and variation in drug content of tablets, (2) unless the drug itself is easily compressible, the amount present is limited to a maximum of 25% of the tablet weight (of course, the amount of vehicle and the weight of the tablet may be increased to reduce the percentage of active ingredient. Then there arises a question of economics and size of the tablet, a question that may be resolved only by wet granulation.), (3) the drug may interact with the vehicle, such as amine compounds do with spray-dried lactose, and (4) static charges which may develop on the drug during combination and mixing may prevent uniform distribution.
In light of the limitations mentioned hereinabove, the great percentage of tabletting operations, therefore, have been forced to resort to other formulation techniques such as the wet and dry granulation methods. Thus, there is a continued search for an improved direct compression tabletting composition capable of being employed as a binder in the preparation of tablets by direct compression which are rapidly disintegrative, resistant to breakage and crumbling and compatible with the active material incorporated therein which forms the basis of the composition's utility.
A more detailed description of the tabletting art is discussed, for example, in "Remington's Pharmaceutical Sciences" Mack Publishing Co. (1965) chapter 39, as well as in U.S. Pat. Nos. 3,305,447 and 3,622,677.
Crystalline sugars used in the food and pharmaceutical industries are generally of two major types. The first type is sucrose derived from sugar cane or sugar beets. The second type is dextrose generally produced by the hydrolysis of starch to the monosaccharide. The art has developed many methods, now considered conventional, for crystallizing raw sugars. One of the most common of these methods comprises first providing an uncrystallized raw sugar in solution form, next concentrating the solution to supersaturation, and then seeding the super-saturated solution with already formed sugar crystals. By subsequent cooling of the solution, new crystals form and grow. After formation of the crystals, the remaining mother liquor is seperated from the crystals. The crystals are then washed and dried to yield the final crystalline sugar product.
The prior art further discloses the use of corn syrup solids having a dextrose equivalent of from 15 to 60, as described in British Patent No. 1,063,535, issued to Huste et al., as an agglomerating agent. However, the corn syrup solids described in Huste et al, by virture of the method of their preparation, have a descriptive ratio less than 2; and, accordingly, tend to by hygroscopic. The descriptive ratio is herein defined as a starch hydrolysate having the sum of the percentages (dry basis) of saccharides therein with a degree of polymerization of 1 to 6 divided by the D.E.
U.S. Pat. No. 3,560,343 to Armbruster et al., discloses a method for preparing low D.E. starch hydrolysates by first treating an aqueous slurry of starch with an acid at elevated temperatures followed by enzymatic saccharification with bacterial alpha-amylase. The products of this unique process are characterized as having a descriptive ratio of at least about 2. The products are disclosed as being useful for many purposes including agglomeration and tabletting, although the specific mode of use thereof is not disclosed in the patent.
Commercial acceptability of an agglomerated sugar is heavily dependent upon its degree of resistance to caking, flowability, agglomerate strength and low dusting characteristics as well as its ability, when used in edible tablet form, to form a strong, easily compressible, tablet of a desired density. Generally speaking, it is believed that for any given agglomerated sugar, agglomerate particle size plays an important role in achieving acceptable levels of these desired characteristics. For example, for many agglomerated sugars, as particle (agglomerate) diameter decreases, losses relating to tablet breakage, dusting, etc. increase exponentially and production decreases. Further, and for the same and other agglomerated sugars, as the particle (agglomerate) diameter decreases, the weight and volume of a tablet increases, thus resulting in a loss of compressibility at constant volume of fill. The problem of dusting, breakage, and compressibility therefore may generally be minimized for any given system using a particular agglomerating agent when forming edible tablets thereof, if the agglomerated particles therein are relatively large, usually above about 200 microns and preferably above about 400 microns. In practice, if an agglomerated sugar product using any particular agglomerating agent has a conventional screen profile wherein a substantial portion of the agglomerated sugar particles are caught by the screens having a mesh size of about 65 or more (i.e., having mesh numbers lower than 65), the agglomerated sugar exhibits characteristics which are particularly desirable for tablets.
When using heretofore conventional agglomerating agents, acceptable levels of screen profiles, agglomerate characteristics, and edible tablet characteristics have been achieved only with difficulty and by using large amounts of agglomerating agents and water. In certain instances, such as when sucrose or blends of sucrose and dextrose were sought to be agglomerated, agglomeration has either failed entirely or the agglomerates were only, in rare instances, of an acceptable quality and were also generally non-reproducible. In many instances when dextrose was agglomerated, the agglomerated product formed was only of low standards. Such results obviously present a very real problem to the industry as a whole.